Compositions for Modulating Lipoxygenase and Methods of Using Same

Abstract

Compositions for inhibiting lipoxygenase enzymes (e.g., human epithelial 12/15-lipoxygenase (12/15-LOX) are provided. Compositions according to certain embodiments include a first solvent, a second solvent and a lipoxygenase inhibitor. In certain instances, the lipoxygenase inhibitor is present in the composition (e.g., compositions formulated for intravenous administration) at a concentration of 30 mg/mL or greater. Methods for treating or preventing a lipoxygenase (e.g., human epithelial 12/15-lipoxygenase (12/15-LOX))-mediated disease or disorder are also provided.

What is claimed is: 
     
         1 . A composition comprising:
 a solvent component comprising:
 a first solvent selected from the group consisting of dimethylacetamide (DMA), diethylacetamide (DEA), dimethylsulfoxide (DMSO), a polyoxyethylene ester of 12-hydroxysteraric acid, a polyethoxylated castor oil, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, a propylene glycol caprylate, a diethylene glycol monomethyl ether, a caprylocaproyl macrogolglyceride, a polyoxyl-6 glyceride and a propylene glycol monolaurate; and 
 a second solvent comprising a polyethylene glycol; and 
   a lipoxygenase inhibitor,   wherein the lipoxygenase inhibitor is present in the composition at a concentration of 30 mg/mL or greater.   
     
     
         2 . The composition according to  claim 1 , wherein the first solvent and second solvent are present in the composition at a ratio of from 5:95 to 50:50. 
     
     
         3 . The composition according to any one of  claims 1-2 , wherein the lipoxygenase inhibitor is present in the composition at a concentration of 50 mg/mL or more. 
     
     
         4 . The composition according to any one of  claims 1-3 , wherein the lipoxygenase inhibitor is a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, in which: 
         X is O or S; 
         R 11  is an aryl, heteroaryl, cyclyl, or heterocyclyl, each of which can be optionally substituted; and 
         R 12  and R 13  are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, acyl, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be optionally substituted 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The composition according to  claim 4 , wherein the lipoxygenase inhibitor is a compound of Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, in which: 
         X is O or S; 
         R 12  and R 13  are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, acyl, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be optionally substituted 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The composition according to  claim 5 , wherein the compound is selected from the group consisting of: 5-(methylamino)-2-naphthalen-1-yl-1,3-oxazole-4-carbonitrile (ML351), 2-(2,3-dichlorophenyl)-5-(methylamino)-1,3-oxazole-4-carbonitrile, 2-(3,4-dichlorophenyl)-5-(methylamino)-1,3-oxazole-4-carbonitrile, 5-(methylamino)-2-naphthalen-1-yl-1,3-thiazole-4-carbonitrile or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The composition according to any one of  claims 1-3 , wherein the lipoxygenase inhibitor is a compound of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is selected from O and S; 
         R 1 , R 2 , and R 3  are each independently selected from halo, CN, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, and C 1-3  haloalkoxy; 
         R 4  is selected from H, C 1-3  alkyl, and HO—C 1-3  alkylene; 
         R 5  is selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C(O)OR a1 , 
         C(O)N(R a1 ) 2 , P(═O)(OR a1 ) 2 , and C(O)R 1 ; wherein said C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl are each optionally substituted with a substituent selected from OR a1  and OP(═O)(OR a1 ) 2 ; 
         each R a1  is independently selected from H, C 1-6  alkyl, C 6-10  aryl, C 1-6  alkyl-C 6-10  aryl, and C 1-6  alkyl-C 6-10  aryl-C 1-6  alkyl, wherein said C 1-6  alkyl, C 6-10  aryl, C 1-6  alkyl-C 6-10  aryl, and C 1-6  alkyl-C 6-10  aryl-C 1-6  alkyl are each optionally substituted with a substituent selected from amino, C 1-6  alkylamino, (C 1-6  haloalkyl)amino, di(C 1-6  alkyl)amino, (C 1-6  alkyl)(C 1-6  haloalkyl)amino, (C 6-10  aryl)amino, (C 6-10  aryl)(C 1-6  alkyl)amino, (5-6-membered heteroaryl)amino, (5-6-membered heteroaryl)(C 1-6  alkyl)amino, C 6-10  aryl, 4-6 membered heterocycloalkyl, 5-6-membered heteroaryl, and OR a2 , wherein said C 6-10  aryl, 4-6 membered heterocycloalkyl, and 5-6-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, carboxy, and halo; 
         each R a2  is independently selected from H, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy-C 1-3  alkyl, 4-7 membered heterocycloalkyl-C 1-3  alkyl, 5-6-membered heteroaryloxy-C 1-3  alkyl, C 6-10  aryl, and 5-6-membered heteroaryl, wherein said C 6-10  aryl and 5-6-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-3  alkoxy, C 1-3  haloalkoxy, C 1-3  alkyl, and C 1-3  haloalkyl; and 
         R b1  is C 1-6  alkyl, optionally substituted with a substituent selected from amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, and 4-7 membered heterocycloalkyl ring comprising at least one N atom, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The composition according to  claim 7 , wherein the lipoxygenase inhibitor is selected from the group consisting of 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The composition according to any one of  claims 1-3  wherein the lipoxygenase inhibitor is a compound of Formula (III): 
       
         
           
           
               
               
           
         
         where R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from hydrogen, hydroxy, alkoxy, amine, cyano, thiol, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
         R A  is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, 
         or a salt, solvate or hydrate thereof. 
       
     
     
         10 . The composition according to  claim 9 , wherein R A  is selected from the group consisting of 2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 2-thiophene, 4-methyl-2-benzothiazole, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 5-phenyl-2-thiazole, 4,5-methyl-2-thiazole, 5-methyl-3-isoxazole, 3-methoxy-phenyl, 3-quinolone, 8-isoquinolone, phenyl, 1-naphthalene, 2-naphthalene, 1,4-bi-phenyl, 1.3-bi-phenyl, 3-piperazine-phenyl, 4-piperazine-phenyl, 4-piperidine-phenyl, 4-piperazine-3-pyridine, 6-methyl-3-pyridine, 2-pyridine, 3-pyridine, 2-pyrimidine, 3-tert-butyl-phenyl, 6-methoxy-2-benzothiazole, 4-phenyl-2-thiazole, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, 3-piperidine-phenyl, 3-isopropyl-phenyl and 6-F-2-benzothiazole. 
     
     
         11 . The composition according to  claim 9 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The composition according to any one of  claims 1-3 , wherein the lipoxygenase inhibitor is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from hydrogen, hydroxy, alkoxy, amine, cyano, thiol, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
         X is S or O; 
         the A ring is a substituted or unsubstituted 5 to 12 membered ring; 
         n is an integer from 0 to 12; and 
         each R a  is independently selected from hydrogen, hydroxy, alkoxy, amine, cyano, thiol, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, 
         or a salt, solvate or hydrate thereof. 
       
     
     
         13 . The composition according to  claim 12 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The composition according to  claim 12 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising:
 a composition according to any one of claims  1 - 14 ; and   a pharmaceutically acceptable excipient.